Abstract
The endoplasmic reticulum (ER) plays a pivotal role in protein synthesis by attaching the carbohydrate side chain of the glycoprotein to the peptide backbone and formation of a disulfide bond, producing the complex conformation of the protein. Dysfunction of ER caused by ischemia is linked to neuronal cell damage. The decrease in amino acid, glucose and Ca2+ levels in ER cause immature protein production, leading to ER stress. Under this condition, the ER chaperone GRP78, some of which is usually bound to the kinase of PERK, ATF6 and IRE1 is dissociated and used for refolding the abnormal protein. This process activates these kinases, leading to induced expression of the ER stress gene (grp78) . Nevertheless, PERK phosphorylates eIF2α, shuts down translation, and stops protein synthesis. If the ischemia is strong enough, protein synthesis will never recover, even though the ER stress genes are up-regulated. When neuronal cells are preconditioned, GRP78 increases with reduction of phosphorylation of eIF2, and protein synthesis recovers after ischemia. Because impairment of ER function triggers secondary mitochondrial dysfunction, the preservation of ER function with up-regulation of chaperones using valproic acid may provide a substantial protective effect to the neuronal cells.
